Published OnlineFirst November 6, 2015; DOI: 10.1158/1078-0432.CCR-15-1588 Clinical Trial Brief Report Clinical Cancer Research An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib Christina Danial, Kavita Y. Sarin, Anthony E. Oro, and Anne Lynn S. Chang Abstract Purpose: To assess the tumor response to the smoothened sive disease with sonidegib. Three patients experienced stable (SMO) inhibitor, sonidegib (LDE225), in patients with an disease and discontinued sonidegib either due to adverse events advanced basal cell carcinoma (BCC) resistant to treatment with (n ¼ 1) or due to election for surgery (n ¼ 2). The response of one vismodegib (GDC0449). patient was not evaluable. SMO mutations with in vitro data Experimental Design: Nine patients with an advanced suggesting resistance to Hh pathway inhibition were identified BCC that was previously resistant to treatment with vismode- in 5 patients, and none of these patients experienced responses gib were given sonidegib in this investigational, open- while on sonidegib. label study. Tumor response was determined using the Conclusion: Patients with advanced BCCs that were response evaluation criteria in solid tumors. SMO mutations previously resistant to treatment with vismodegib similarly were identified using biopsy samples from the target BCC demonstrated treatment resistance with sonidegib. Patients location. who have developed treatment resistance to an SMO inhibitor Results: The median duration of treatment with sonidegib was may continue to experience tumor progression in response to 6 weeks (range, 3–58 weeks). Five patients experienced progres- other SMO inhibitors. Clin Cancer Res; 1–5. Ó2015 AACR. Introduction Sonidegib (LDE225) is a new SMO inhibitor approved in 2015 by the FDA for locally advanced BCCs. Clinical trials have shown Smoothened (SMO) inhibitors are a new class of drugs for the its efficacy against locally advanced BCCs (6, 7). Sonidegib blocks treatment of advanced basal cell carcinomas (BCC) that include hedgehog signaling by selective inhibition of SMO, even though locally advanced and metastatic tumors (1). Vismodegib its chemical structure is different from vismodegib (8). Although (GDC0449) is a first-in-class SMO inhibitor approved by the antitumor activity has been reported in patients with advanced FDA for the treatment of both locally advanced and metastatic BCCs who were treated with sonidegib, an in vitro study has shown BCCs in 2012 (1, 2). Although patients treated with vismodegib that cells with SMO mutations display resistance to sonidegib can have partial and complete responses, more than 50% of (4, 6, 7). The purpose of this investigator initiated open-label patients are refractory to treatment, whereas over 20% of initial study was to assess the tumor response to sonidegib in patients responders develop resistance and experience disease progression with an advanced BCC that previously was resistant to treatment or recurrence (2, 3). Recently, a subset of mutations in the drug with vismodegib. target, SMO, has been identified in advanced BCCs resistant to vismodegib (4, 5). Acquired SMO mutations maintain hedgehog signaling by either impairing drug binding or inducing constitu- Materials and Methods tive activity of SMO, resulting in resistance to vismodegib (4, 5). Study patients These SMO mutations have also been shown to display functional Approval was obtained from the Institutional Review Board, resistance to vismodegib in vitro (4). The clinical outcome of a and written informed consent was obtained from all participants. chemically distinct SMO inhibitor on an advanced, vismodegib- An open-label study was conducted at a single academic institu- resistant BCC in vivo is unknown. tion from October 2011 to December 2013. This study was registered as NCT01529450 on clinicaltrials.gov. Department of Dermatology, Stanford University School of Medicine, Inclusion criteria Stanford, California. Eligible patients were those with advanced (locally advanced or Note: Supplementary data for this article are available at Clinical Cancer metastatic) BCC that clearly demonstrated either primary or Research Online (http://clincancerres.aacrjournals.org/). secondary treatment resistance with vismodegib, as documented Corresponding Author: Anne Lynn S. Chang, Stanford University School of by their previous treating physician. Composite response end- Medicine, 450 Broadway Street Pavilion C, 2nd Floor MC 5334, Redwood City, point incorporating RECIST 1.0 (1) had been used to quantita- CA 94063. Phone: 650-721-7151; Fax: 650-721-3464; E-mail: tively define resistance to vismodegib (Supplementary Fig. S1). [email protected] Primary resistance was defined as stable or progressive disease; doi: 10.1158/1078-0432.CCR-15-1588 secondary resistance was defined as progressive disease after Ó2015 American Association for Cancer Research. initially demonstrating stable, partial, or complete response. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst November 6, 2015; DOI: 10.1158/1078-0432.CCR-15-1588 Danial et al. Histologic confirmation of the target advanced BCC was required phy (WHO criteria; ref. 9). In cases of clinically visible BCC, where before enrollment into this study. In this study, patients required the tumor borders were complex, clean plastic grids were used to measurable, evaluable disease as defined by modified RECIST v. trace the edges of the tumors to identify the longest diameter 1.1 criteria and standard and annotated color photography (9). (Fig. 1A). Color photographs of target lesions with rulers in the Patients with basal cell nevus syndrome could enroll if they met plane of focus were taken at each clinic visit, and longest diameters inclusion criteria. identified (Fig. 1B and C). In cases where tumor borders were unclear from visual inspection of photographs, the plastic grid Exclusion criteria tracings were inspected to provide additional information on Patients were excluded from enrollment if they previously had tumor borders. Sonidegib was administered until either disease been treated with sonidegib; had completed antitumor therapy progression, as defined by RECIST v 1.1; intolerable toxicity, or less than 28 days before sonidegib initiation; or were on concur- patient or physician request to discontinue (9). Dose reduction rent antitumor therapy. was not permitted. Study design Genetics This was an open-label, investigator-initiated study. Patients DNA from the target BCCs after vismodegib exposure, but received 800 mg oral sonidegib once daily, with treatment cycles before study entry was isolated and subjected to high-depth defined as every 28 days. This dose of sonidegib has been used in sequencing for the entire SMO coding region. Briefly, five to eight other clinical trials (7). Clinic visits and tumor assessments 10-mm sections were obtained from the formalin-fixed, paraffin- occurred every 1 to 2 treatment cycles, or sooner, if necessary, as embedded tumor block and DNA was isolated using the Qiagen deemed by the investigator. Clinic visits included medical history, DNeasy Blood and Tissue Kit according to the manufacturer's vital signs, physical examination, and adverse event recording and protocol (Qiagen). The exonic regions of SMO were amplified grading using the National Cancer Institute's Common Termi- using the Access Array platform (Fluidigm) in a multiplex format nology Criteria for Adverse Events version 4.0 (10). with genomic DNA (100 ng) according to the manufacturer's recommendation (Ambry Genetics). The multiplexed library Efficacy analysis pools were then subjected to deep sequencing using the Illumina Patients receiving greater than or equal to one dose of sonidegib MiSeq platform. FASTQ files were generated for the raw data and and having at least one follow-up tumor assessment were includ- 150 bp reads aligned to the human reference genome sequence ed in the efficacy-evaluable population. Tumor responses were (hg19) using the Burrows-Wheeler Aligner (BWA). Samtools investigator-assessed according to modified RECIST v. 1.1, which mpileup was used to call variants. Only bases meeting the min- was a composite multimodal evaluation to integrate imaging by imum base quality score of 20 from reads meeting the minimum RECIST 1.1 criteria and standard and annotated color photogra- mapping quality score of 20 were considered, and a minimum A BC Figure 1. Target BCC size determination of clinically visible lesions, and overall responses of enrolled subjects. Color photographs were taken of all clinically visible lesions with a ruler in the plane of the lesion. A, in cases D where the tumor borders are complex, clean plastic 60 # No SMO grids were placed over the lesions and traced to mutation with known Q477E S533N document the longest diameter. B, photograph of functional resistance 50 target lesion in a subject before study start. C, * Nonevaluable photograph of same target lesion after 6 weeks of 40 sonidegib. Arrows indicate areas of tumor growth. D, D473H D473G change in target tumor diameter from baseline (%) 30 # after sonidegib. None of the patients met the 30% partial response (top gray dotted line) per RECIST, 20 version 1.1. SMO mutations that are known to lead to functional resistance in vitro found in individual tumors 10 No are annotated for each patient. useable W535L ## 0 * tissue * –10 –20 Subject 1 Subject 2 Subject 3 Subject